Factor XII Inhibitor for Surface Initiated Thrombosis

项目摘要 某些挽救生命的干预措施，如体外循环、体外膜 氧合(ECMO)、血液透析或脑室辅助装置(VAD)泵需要使用肝素来 保持血液流经装置和/或防止下游血栓形成并发症。几个 其他侵入性血管手术也使用暂时性抗凝，例如在假体期间和之后。 血管植入术。不幸的是，肝素等抗血栓药物无意中将重要的 止血的分子机制，并可具有严重的剂量限制出血毒性。因此， 必须限制抗凝水平，以平衡出血和血栓形成的风险。结果, 设备故障和血栓并发症可能是频繁和毁灭性的。我们最近的研究表明 凝血因子XII(FXII)促进血栓形成的进展，因此是一种潜在的靶点 新型抗血栓药物。由于数据还表明FXII对止血没有贡献，并且 FXII缺乏是哺乳动物的一种无症状状态，抑制FXII不太可能有显著的不利影响 效果。在这个IIB期小市场项目中，我们将继续开发我们的创新抗凝药物 适用于ECMO和其他出血风险较高的血栓症适应症。我们目前正在进行 计划在第二阶段B开始时达到我们所有的第一阶段/第二阶段快速通道里程碑，并已：1)确认 在我们的ECMO模型中靶向FXII是抗血栓的，并且在没有 止血损害可检测到的增加，2)人源化我们的鼠抗FXII抗体，现在 指定为AB054，以及3)完成了稳定的制造单元线的开发，该制造单元线正在用于 产生大量的AB054毒理物质。我们还开发了支持IND的GLP毒性协议用于研究 这将在Charles River实验室(里诺，内华达州)在阶段开始时发布我们的毒理学批次时开始 IIB。这个小市场项目，再加上我们的担保配对资金，将为 继续进行IND应用的产品开发和ECMO适应症的临床试验。我们的 具体目的是：1)测定人源化抗FXII抗体的毒性，AB054；2)制造 CGMP批次的AB054用于人体研究，以及3)启动一期临床试验以评估安全性、耐受性、 AB054的药代动力学和药效学。该项目的成功将推动AB054迈向 我们建议的初始小市场进入适应症的第二阶段人类概念验证临床试验：安全 ECMO期间的抗凝，肝素会导致出血，经常无法维持设备的灌流。

Project Summary Certain life-saving interventions such as cardiopulmonary bypass (CPB), extracorporeal membrane oxygenation (ECMO), hemodialysis, or ventricular assist device (VAD) pumps require the use of heparin to maintain blood flow through the devices and/or to prevent downstream thromboembolic complications. Several other invasive vascular procedures also utilize temporal anticoagulation, such as during and after prosthetic vascular graft implantation. Unfortunately, antithrombotic agents such as heparin inadvertently target vital hemostatic molecular mechanisms and can have severe dose-limiting hemorrhagic toxicity. Consequently, the level of anticoagulation must be limited to balance the risk of bleeding with that of thrombosis. As a result, device failure and thrombotic complications can be frequent and devastating. Our recent studies suggest that coagulation factor XII (FXII) contributes to the progression of thrombosis, and thereby is a potential target for a new class of antithrombotic drugs. Since data also suggests that FXII does not contribute to hemostasis, and FXII deficiency is an asymptomatic condition in mammals, FXII inhibition is unlikely to have significant adverse effects. In this Phase IIB Small Market project, we will continue to develop our innovative anticoagulant drug candidate for use during ECMO and other thrombotic indications with a high bleeding risk. We are currently on track to reach all of our Phase I/II Fast-Track milestones by the beginning of Phase IIB and have: 1) confirmed that targeting FXII in our ECMO model is antithrombotic and improves the effectiveness of heparin without a detectable increase in hemostasis impairment, 2) humanized our lead murine anti-FXII antibody, which is now designated as AB054, and 3) completed development of a stable manufacturing cell line that is being used to produce a toxicology lot of AB054. We have also developed IND-enabling GLP toxicity protocols for studies that will commence at Charles River Labs (Reno, NV) upon release of our toxicology lot at the start of Phase IIB. This Small Market project, combined with our secured matching funds, will provide essential support for continued product development towards an IND application and clinical trials for the ECMO indication. Our specific aims are to: 1) determine the toxicity of the humanized anti-FXII antibody, AB054, 2) manufacture a cGMP lot of AB054 for human studies, and 3) initiate a phase 1 clinical trial to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of AB054. Success of this project will propel AB054 towards a phase 2 human proof-of-concept clinical trial in our proposed initial small market entry indication: safe anticoagulation during ECMO, where heparin can cause bleeding and often fails to sustain device perfusion.